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Philos Trans R Soc Lond B Biol Sci
2024 May 06;3791901:20230074. doi: 10.1098/rstb.2023.0074.
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The roles of ABCB1/P-glycoprotein drug transporters in regulating gut microbes and inflammation: insights from animal models, old and new.
Stoeltje L
,
Luc JK
,
Haddad T
,
Schrankel CS
.
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Commensal enteric bacteria have evolved systems that enable growth in the ecologic niche of the host gastrointestinal tract. Animals evolved parallel mechanisms to survive the constant exposure to bacteria and their metabolic by-products. We propose that drug transporters encompass a crucial system to managing the gut microbiome. Drug transporters are present in the apical surface of gut epithelia. They detoxify cells from small molecules and toxins (xenobiotics) in the lumen. Here, we review what is known about commensal structure in the absence of the transporter ABCB1/P-glycoprotein in mammalian models. Knockout or low-activity alleles of ABCB1 lead to dysbiosis, Crohn's disease and ulcerative colitis in mammals. However, the exact function of ABCB1 in these contexts remain unclear. We highlight emerging models-the zebrafish Danio rerio and sea urchin Lytechinus pictus-that are poised to help dissect the fundamental mechanisms of ATP-binding cassette (ABC) transporters in the tolerance of commensal and pathogenic communities in the gut. We and others hypothesize that ABCB1 plays a direct role in exporting inflammatory bacterial products from host epithelia. Interdisciplinary work in this research area will lend novel insight to the transporter-mediated pathways that impact microbiome community structure and accelerate the pathogenesis of inflammatory bowel disease when perturbed. This article is part of the theme issue 'Sculpting the microbiome: how host factors determine and respond to microbial colonization'.
Figure 1. . The ABC transporter ABCB1/P-gp acts as a xenobiotic gatekeeper in gut epithelia. Multiple small molecules generated by commensal or opportunistic pathogens can enter the host gut epithelia by various mechanisms ('1'; see box 1 in main text). ABCB1 protein (also known as P-glycoprotein; encoded by the mdr1a gene), is proposed to export (green arrow) small molecules generated from luminal bacteria ('2'). Nucleotide binding domains (NBDs) form an ATP-binding cassette region that catalyzes the efflux of interloping xenobiotics out of host epithelial cells.
Figure 2. . A simple echinoderm model for testing the regulation and function of ABC transporters in host-microbe interactions. (a) The sea urchin develops a feeding larva with a tripartite gut by 48 hours (Lytechinus pictus) to 72 hours (Strongylocentrotus purpuratus) post-fertilization. Millions of embryos are generated in a single spawn. ABC transporters are placed in specific sections the developing gut tube (mg, midgut; hg, hindgut) and concentrate in the larval gut. Scale bars: 50 μm. Modified from Schrankel & Hamdoun 2021. (b) An organismal-wide response is easily imaged in optically clear larvae. Gut epithelial responses are facilitated by epithelial recognition of microbes. In the case of dysbiosis or infection, epithelial cytokine signaling activates immune cell migration and effector gene responses. Additional advantages of the sea urchin system are listed. PWs, pathways.
Figure 3. . Inflammatory phenotypes suggest a buildup of bacterial metabolites in CRISPR/Cas9-mediated ABCB1 knockout in the sea urchin. (a) Magnified view of larval sea urchin guts in cross section. ABCB1 knockouts (KO) exhibit thickened epithelia (outlined in dotted white line) and gut-localized pigment cells prior to exposure to V. diazotrophicus. These phenotypes were exacerbated upon exposure to the pathogenic Vibrio species. Scale bars: 50 μm. Modified from Fleming et al. 2021. (b) IL-17 cytokines remain activated 48 hours post bacterial exposure in ABCB1 KOs, whereas wild type (WT) animals have resolved a spike in IL-17 expression. Modified from Fleming et al. 2021. (c) Schematic for hypothesized interactions between ABCB1 and luminal bacteria. KO, knockout; PC, pigment cell (larval immunocyte); WT, wild type. These phenotypes extend to other animal models (see main text).
Figure 4. . Future directions for identifying the bacterial-derived compounds that are ABCB1 substrates. Metagenomic and metabolomic profiling, combined with the advent of increasingly powerful 3D-modeling and prediction approaches, can be used in the sea urchin system (pictured on the left), given the extreme fecundity of animals created per spawn. These techniques can be applied to other model organisms or human patients and datasets to identify areas of conservation and differences in ABCB1 function against bacterial small molecules. LC-MS, liquid chromatography-mass spectrometry.
